Document Detail

Endothelin and endothelin antagonists in hypertension.
MedLine Citation:
PMID:  9886874     Owner:  NLM     Status:  MEDLINE    
The endothelins (ET) are potent 21-amino-acid vasoconstrictor peptides produced in many different tissues, particularly in the endothelium of blood vessels. ET-1 is the main endothelin secreted by the endothelium, and acts in a paracrine or autocrine fashion on blood vessels by interacting with ETA or ETB receptors on smooth muscle to stimulate contraction or on ETB receptors on endothelial cells to induce the release of vasorelaxants (nitric oxide and prostacyclin). Production of ET-1 is enhanced in several experimental models of hypertension in the rat, such as sodium-sensitive forms, e.g. deoxycorticosterone acetate (DOCA)-salt hypertensive, DOCA-salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, as well as other models such as stroke-prone SHR, angiotensin II-infused rats and fructose-fed rats, and possibly 1-K 1C Goldblatt hypertensive rats. In contrast, SHR, 2-K 1C Goldblatt hypertensive rats and nitric oxide-deficient (L-NAME-treated) hypertensive rats do not exhibit an ET-1 component. Endothelin dependency is manifested by excessive vascular growth, particularly in small arteries, and blood pressure lowering and regression of vascular growth after treatment with endothelin antagonists. The latter may be combined ETA/ETB or selective ETA antagonists, of which several are orally active and already in clinical development. In humans, endothelin-dependent vascular tone has been shown in studies of forearm blood flow. Enhanced expression of ET-1 mRNA has been demonstrated in the endothelium of small arteries of patients with moderate to severe hypertension. In a 4-week trial the combined ETA/ETB antagonist bosentan reduced the blood pressure of essential hypertensive patients equally to enalapril. Bosentan improved hemodynamics in patients with heart failure in acute and 2-week-long studies. Endothelin antagonists also offer promise in a rapidly fatal condition, primary pulmonary hypertension. Thus, the endothelin system appears to be involved in different forms of cardiovascular disease in experimental animals and humans, and its interruption offers great promise as a new therapeutic intervention in hypertension, heart failure and other diseases.
E L Schiffrin
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Publication Detail:
Type:  Lectures; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Journal of hypertension     Volume:  16     ISSN:  0263-6352     ISO Abbreviation:  J. Hypertens.     Publication Date:  1998 Dec 
Date Detail:
Created Date:  1999-04-02     Completed Date:  1999-04-02     Revised Date:  2013-06-18    
Medline Journal Info:
Nlm Unique ID:  8306882     Medline TA:  J Hypertens     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1891-5     Citation Subset:  IM    
Clinical Research Institute of Montréal (IRCM), Québec, Canada.
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MeSH Terms
Antihypertensive Agents / therapeutic use
Cardiovascular System / physiopathology
Disease Models, Animal
Endothelin-1 / antagonists & inhibitors*,  physiology*
Hypertension / drug therapy,  etiology,  physiopathology*
Receptor, Endothelin A
Receptor, Endothelin B
Receptors, Endothelin / antagonists & inhibitors,  physiology
Sulfonamides / therapeutic use
Reg. No./Substance:
0/Antihypertensive Agents; 0/Endothelin-1; 0/Receptor, Endothelin A; 0/Receptor, Endothelin B; 0/Receptors, Endothelin; 0/Sulfonamides; Q326023R30/bosentan

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